Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition

Cole, David K., Edwards, Emily S.J., Wynn, Katherine K., Clement, Mathew, Miles, John J., Ladell, Kristin, Ekeruche, Julia, Gostick, Emma, Adams, Katherine J., Skowera, Ania, Peakman, Mark, Wooldridge, Linda, Price, David A., and Sewell, Andrew K. (2010) Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition. Journal of Immunology, 185 (4). pp. 2600-2610.

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Improving T-cell antigens by altering MHC anchor residues is a common strategy used to enhance peptide vaccines but there has been little assessment of how such modifications affect TCR binding and T-cell recognition. Here, we use surface plasmon resonance and peptide-MHC tetramer binding at the cell surface to demonstrate that changes in primary peptide anchor residues can substantially and unpredictably alter TCR binding. We also demonstrate that the ability of TCRs to differentiate between natural and anchor-modified heteroclitic peptides distinguishes T-cells that exhibit a strong preference for either type of antigen. Furthermore, we show that anchor-modified heteroclitic peptides prime T-cells with different TCRs compared to those primed with natural antigen. Thus, vaccination with heteroclitic peptides may elicit T-cells that exhibit suboptimal recognition of the intended natural antigen and, consequently, impaired functional attributes in vivo. Heteroclitic peptide-based immune interventions therefore require careful evaluation to ensure efficacy in the clinic.

Item ID: 45237
Item Type: Article (Research - C1)
ISSN: 1550-6606
Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Medical Research Council (MRC), Wellcome Trust (WT), Leverhulme Trust (LT), Department of Health (DH), National Institute for Health Research Biomedical Research Centre (NIHRBRC), King's College, London (KCL), Juvenile Diabetes Research Foundation (JDRF)
Projects and Grants: BBSRC Grant BB/H001085/1, DH/NIHRBRC/KCL/JDRF International Grant 7-2005-877
Date Deposited: 06 Sep 2016 04:43
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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